1. Field of the Invention
The invention relates to compositions, which provide sustained release (SR), extended release (ER), or controlled release of highly water-soluble pharmaceutically active agents, including those, which are categorized as highly water-soluble, with a short metabolic half-life, and therapeutically efficacious at a high daily dose.
2. Description of the Related Art
It is difficult to provide a sustained release oral dosage form for drugs of a high-solubility, a short half-life, and a high dose. A drug of a high water-solubility can dissolve in water or gastrointestinal milieu readily and tends to release from its dosage form in a burst and thus is absorbed quickly, leading to a sharp increase in the drug blood concentration. Compared to less soluble drugs, it is often difficult to sequester a highly water soluble drug in the dosage form (such as a tablet) and retard the drug release, especially when the drug dose is high.
If the drug of a high water-solubility is also of a short half-life (i.e., quickly metabolized in the body thereby losing its activity), the drug would remain in the blood for only a short time, resulting in a short duration of action. For such a drug, a multiple daily dosing regimen (three, four or more times a day) is necessary to maintain a steady drug concentration in the blood above its effective concentration level. A multiple daily dosing is inconvenient and reduces the patient compliance significantly. A sustained release dosage form, which allows for a reduced dosing frequency such as once a day, is thus much desired.
If the drug of a high water-solubility and a short half-life is also a high dose drug (e.g., those that require a daily dose exceeding 500 mg), it becomes even more challenging to develop sustained release oral dosage forms. For short half-life drugs, to provide a once-a-day tablet, it requires not only that a large amount of drug be incorporated in a dosage unit to provide the daily dose, but also that the dosage units be small in size to allow for ease of swallowing by the human or non-human subject. The requirement for smaller sizes would leave little space in the dosage unit for other ingredients needed to control the release of the drug. The size of the dosage unit becomes even more critical with highly water-soluble drugs since even a larger amount of inactive ingredients (e.g., more than 50% of the total weight) is usually needed to provide the sustained release property, according to the conventional SR methods.
Typically, a tablet of a total weight about 1-1.5 g is considered as the largest tablet that can be readily swallowed by a normal adult patient without discomfort, the same limitation applies to veterinary patients such as dogs. So it is important for an SR composition to have not only high drug content (e.g., more than 50% of the total weight) but also a reasonable size.
In summary, the combined features of a high-solubility, short half-life and high dose poses a great challenge in developing an easy-to-swallow and once-a-day or twice-a-day dosage form for many drugs in the category of high-solubility, short half-life and high dose.
Tablets are by far the most popular dosage form for oral administration. Generally, sustained release tablets have been prepared in a number of ways including matrix tablets, coated tablets and combination thereof. In a matrix tablet, the drug is usually mixed with a gelling material, which upon contact with water can form a thick layer of gel that slows down the diffusion of the drug while undergoing slow erosion. Both diffusion and erosion contribute to drug release. A coating can provide both a barrier limiting the erosion and drug release from its core.
Matrix tablets are probably the most important sustained release form in which the sustain-release components are commonly selected from hydrogel polymers such as cellulose polymer or other synthetic water-soluble polymers such as polyethylene oxides (polyox) or methacrylate polymers (carbomers). Non-ionic cellulose ethers, and more frequently, hydroxypropyl methylcellulose (HPMC, hypromellose) have been widely used for applications in oral SR systems.
Matrix tablets are of particular interest for veterinarian applications because the patients (e.g., dogs, cats, horses, etc.) are likely to chew the tablets. Therefore, a preferable tablet form must be able to withstand some degree of pulverization without losing its sustained-release property. In comparison with a coated sustained release tablet (i.e., sustained release controlled by only or primarily through a layer of coating), matrix tablets are advantageous because an SR coating of a coated sustained release tablet, which is the rpimary barrier, may be destroyed easily by animal chewing, and the bulk of the drug content is thus at risk of being released as a burst, which could be toxic in more serious cases.